French patent FR-A-2 341 578 and European patent EP-A-0 471 609 describe indolizine derivatives which have remarkable pharmacological properties, especially antiarrhythmic properties, since those derivatives have been shown to be capable of suppressing or staving off ventricular and auricular rhythm problems. The majority of the compounds described have electrophysiological properties in classes 1, 2, 3 and 4 of the Vaughan-Williams classification which in addition to their antiarrhythmic properties, indicate their bradycardiac, anti-hypertensive and α and β non-competitive anti-adrenergic properties. Such properties render the compounds in question very useful in the treatment of certain pathological syndromes of the cardiovascular system, in particular in the treatment of angina pectoris, hypertension or ventricular or supraventricular arrhythmia. Similarly, such compounds are used to treat cardiac insufficiency, myocardial infarction complicated or otherwise by cardiac insufficiency, or to prevent post-infarction mortality.
However, such compounds have the disadvantage of being insoluble or only slightly soluble in water, in particular at pH=4 and especially at a physiological pH.
Amiodarone, which is an auricular and ventricular antiarrhythmic which is administered orally and intravenously, is a molecule which is insoluble in water; the injectable solution thus contains solvents such as polysorbate 80 and benzyl alcohol. Such solvents induce hypotensive and negative inotropic effects in patients. The injectable solution also causes local venous intolerances which are prevented by recommending a central injection in a specialized hospital environment.
Dronedarone, a derivative of benzofuran, contains no iodine in its chemical structure, in contrast to amiodarone, and is also an auricular and ventricular antiarrhythmic which is administered orally and intravenously. Its low solubility (solubility in water S=0.247 mg/ml at a pH of 3) limits the possibility of preparing and storing it in the form of an injectable substance.
That low solubility substantially limits the possibility of preparing and storing them in the form of an injectable substance.
In the context of the invention, novel indolizine derivatives have now been discovered which have good solubility in water while retaining or even improving their pharmacological properties, especially their antiarrhythmic properties. Their good solubility in water, in particular at pH=4, allows injectable pharmaceutical forms to be produced.
The compounds of the present invention are molecules which are soluble in water which can be administered intravenously in a physiological solution (0.9% sodium chloride) or glucosated, and which have the electrophysiological, haemodynamic and antiarrhythmic properties of amiodarone.
Furthermore, these novel compounds also exhibit good metabolic stability.
Thus, the invention proposes indolizine derivatives comprising an aminoalkylbenzoyl chain represented by formula (I) below.
Thus, the present invention concerns novel indolizine derivatives with general formula (I):
in which:X represents a —(CH2)n— radical where n is a whole number from 1 to 6, or a group with formula CH2—Z—(CH2)2—, in which Z represents an O(CH2)m— group in which m is a whole number from 0 to 3; R1 represents a linear, branched or cyclic C1-C8 alkyl radical; Am represents an NR3R4 group in which R3 and R4 are identical or different and independently of each other represent:
a hydrogen atom;
a linear, branched or cyclic C1-C6 alkyl radical or a C1-C3 radical substituted with a C3-C6 cycloalkyl radical;
or a (CH2)l—O—B radical in which B represents a hydrogen atom or a —(CH2)kH alkyl radical, where l and k are whole numbers, l≧2 and l+k≦6;
or R3 and R4 together with the nitrogen atom to which they are attached form a heterocycle containing 4 to 6 links which may optionally contain one or more heteroatoms selected from N and O and optionally carrying one or more substituents selected from a linear, branched or cyclic C1-C6 alkyl radical;R2 represents a hydrogen atom or a linear, branched or cyclic C1-C6 alkyl radical;and their pharmaceutically acceptable salts.
In a first variation, the invention concerns indolizine derivatives as defined above in which X represents a —(CH2)n— radical where n is a whole number from 1 to 6.
In a second variation, the invention concerns indolizine derivatives as defined above in which X represents a group with formula CH2—Z—(CH2)2—, in which Z represents an O(CH2)m— group in which m is a whole number from 0 to 3.
More particularly, the invention concerns indolizine derivatives as defined above, characterized in that X represents a (CH2)n— radical where n is a whole number from 3 to 4.
More particularly, the indolizine derivatives of the invention are characterized in that R1 represents a C1-C4 alkyl radical.
More particularly, the indolizine derivatives of the invention are characterized in that R3 and R4 independently of each other represent a linear C1-C4 alkyl radical.
In particular, the indolizine derivatives of the invention are characterized in that R3 and R4 together form a piperidinyl or piperazinyl group optionally carrying one or more methyl radicals.
In particular, the indolizine derivatives of the invention are characterized in that R2 represents a hydrogen atom.
The compounds of formula (I) can exist in the form of bases or in the form salified with acids or bases, in particular pharmaceutically acceptable acids or bases. Such addition salts form part of the invention.
These salts are advantageously prepared with pharmaceutically acceptable acids, but the salts of other acids that are of use, for example, for the
The compounds of formula (I) can also exist in the form of hydrates or of solvates, i.e. in the form of associations or of combinations with one or more molecules of water or with a solvent. Such hydrates and solvates also form part of the invention.
The invention also pertains to pharmaceutically acceptable salts of compounds with formula (I) formed from an organic or inorganic acid.
Examples of organic salts of this type which may be cited are the malonate, dodecanoate, oxalate, maleate, fumarate, methanesulphonate, benzoate, ascorbate, pamoate, succinate, hexamate, bis-methylenesalicylate, ethanedisulphonate, acetate, propionate, tartrate, salicylate, citrate, gluconate, lactate, malate, cinnamate, mandelate, citraconate, aspartate, palmitate, stearate, itaconate, glycolate, p-aminobenzoate, glutamate, benzenesulphonate, p-toluenesulphonate and theophylline acetate, as well as the salts formed from an amino acid, such as the lysine or histidine salt.
Inorganic salts of this type which may be cited are hydrochlorides, hydrobromides, sulphates, sulphamates, phosphates and nitrates.
More particularly, the invention concerns indolizine derivatives as defined above, characterized in that the pharmaceutically acceptable salt is selected from the oxalate and the hydrochloride.
The invention also pertains to the preparation of compounds with formula (I).
Thus, the present invention concerns a method for preparing derivatives with formula (I) as defined above, comprising the reaction of an amine H—Am with a compound represented by formula (II):
in which Y represents a halogen atom and the other substituents are as defined above.
The invention also concerns a method comprising a method for preparing a compound with formula (II) as defined above and comprising the reaction of a compound represented by formula (III):
with a compound represented by formula (IV):

Thus, in accordance with the invention, compounds with formula (I) in which X represents a —(CH2)n— radical as defined above are prepared in accordance with the following reaction scheme:
in which Y represents a halogen, for example Cl or Br, and n and the R1, R2, Am groups have the same meanings as given above.
Reference may be made to U.S. Pat. No. 6,949,583 for the preparation of the compounds with formula (III).
To prepare compounds with formula (IV), reference may be made to the publication EUR J. MED. CHEM-CHEMICAL THERAPEUTICA, NOVEMBER-DECEMBER 1975-10, No 6, pp 579 to 584 and to LABAZ's U.S. Pat. No. 4,103,012.
Similarly, to prepare indolizine derivatives with formula (I) by condensing a secondary amine with formula H—Am with the chlorinated derivative with formula (II) and to prepare compounds with formula (II) by reacting compounds with formula (III) with derivatives with formula (IV), reference should be made to the document U.S. Pat. No. 4,103,012.
In accordance with the invention, to prepare compounds with formula (I) when X represents a group with formula CH2—Z—(CH2)2—, in which Z represents an O(CH2)m— group as defined above, reference should be made to U.S. Pat. No. 6,949,583 and to Monatsh Chem: 129; 3; 1998; 309-318 and to the following reaction scheme:
in which the groups R1, R2, Am have the same meanings as given above.
The invention also pertains to a pharmaceutical or veterinary composition, characterized in that it contains, as the active principle, at least one indolizine derivative with formula (I) as defined above or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable vehicle or an appropriate excipient.
As an example, the pharmaceutical compositions of the present invention may be formulated for oral, sublingual, subcutaneous, intramuscular, intravenous, transdermal or rectal administration. Preferably, the compositions are present in an injectable form, exploiting the good solubility characteristics of the derivatives of the invention.
Regarding the administration unit, this may take the shape, for example, of a tablet, a dragée, a capsule, a gellule, a powder, a suspension, a syrup or granules for oral administration, a suppository for rectal administration or a solution or suspension for parenteral administration.
The pharmaceutical compositions of the invention may, for example, comprise, per administration unit, 50 to 500 mg by weight of active ingredient for oral administration, 50 to 200 mg of active ingredient for rectal administration and 50 to 150 mg of active ingredient for parenteral administration.
Depending on the administration route selected, the pharmaceutical or veterinary compositions of the invention are prepared by associating at least one of the compounds with formula (I) or a pharmaceutically acceptable salt of that compound with a suitable excipient, the latter possibly being constituted, for example, by at least one ingredient selected from the following substances: lactose, starches, talc, magnesium stearate, polyvinyl pyrrolidone, alginic acid, colloidal silica, distilled water, benzyl alcohol or sweetening agents.
When they are in tablet form, they may be treated so that they have an extended or delayed action and so that they continuously release a predetermined quantity of active principle.
The invention also concerns indolizine derivatives with general formula (I) as defined above for their use as a drug. The present invention thus concerns drugs comprising indolizine derivatives with general formula (I) as defined above.
The indolizine derivatives with general formula (I) of the present invention as defined above may be used to prepare a drug for the treatment of pathological syndromes of the cardiovascular system. More particularly, the indolizine derivatives with general formula (I) of the present invention as defined above may be used to prepare a drug for the treatment of angina pectoris, hypertension, ventricular arrhythmia, supraventricular arrhythmia, in particular auricular fibrillation, cardiac insufficiency, myocardial infarction which may or may not be complicated by cardiac insufficiency or for the prevention of post-infarction mortality.
The results of pharmacological tests carried out to determine the properties of the compounds of the invention as regards the cardiovascular system are recorded below.
I. Ventricular Arrhythmias
This test aims to determine the capacity of the compounds of the invention to protect against arrhythmias caused by re-perfusion of a previously ischaemiated coronary artery. To this end, we used the method set out by MANNING A. S. et al. in Circ. Res. 1984, 55: 545-548 modified as follows:
Firstly, rats sorted into batches were anaesthetized with sodium pentobarbital (60 mg/kg intraperitoneally) then they were intubated to assist respiration.
A cannula was then placed in a jugular vein for intravenous administration, a catheter was placed in a carotid artery to measure the arterial pressure, and cutaneous electrodes were placed to measure the ECG. After equilibrating the parameters, an intravenous dose of the compound to be studied was administered and 5 minutes later, after carrying out a thoracotomy, a loop of ligature was placed around the left anterior descending coronary artery in the immediate proximity of its origin. Thus, that artery was occluded for 5 minutes by tension on the ends of the ligature. Re-perfusion was obtained by releasing the tension.
The arrhythmias induced by that re-perfusion were then evaluated.
An analogous test was carried out after oral administration of the compound. In this case, the study compound was administered 60 to 120 minutes before ligating the left anterior descending coronary artery.
The results of these tests showed that the compounds of the invention, administered in doses in the range 0.3 to 10 mg/kg intravenously and 30 to 100 mg/kg orally, significantly or completely protected the treated animals from ventricular arrhythmia.
II. Antiadrenergic Properties
This test aims to determine the capacity of the compounds of the invention to reduce the increase in blood pressure induced by phenylephrin (anti-α effect) and the acceleration in cardiac frequency induced by isoprenaline (anti-β effect) in a dog which had been anaesthetized beforehand with pentobarbital and chloralose.
Initially, for each dog the dose of phenylephrin (5 μg/kg was determined which provoked an increase in the arterial pressure in the range 25 to 40 mmHg and the dose of isoprenaline (0.5 or 1 μg/kg) which should cause an increase in cardiac frequency in the range 40 to 110 beats/minute.
Every 10 minutes, the doses of phenylephrin and isoprenaline determined in this way were injected alternately and after obtaining two successive reference responses, a dose of the compound to be studied was administered intravenously.
Anti-α Effect
The percentage reduction by the compound of the invention in the hypertension caused compared with the reference hypertension obtained before injecting that compound was recorded.
Anti-β Effect
The percentage reduction in the study compound of the acceleration caused in the cardiac frequency was recorded.
The results of these tests showed that in doses of 3 to 10 mg/kg, the compounds of the invention exhibited anti-α and/or anti-β effects, resulting in reductions in the provoked hypertension and/or the provoked increase in cardiac frequency, of up to 50%.
III. Auricular Arrhythmias
This test aims to evaluate the efficacy of the compounds of the invention as regards auricular arrhythmia (left auricular vulnerability) induced by extra stimuli in the anaesthetized pig using the method described in Naunyn-Schmiedeberg's Arch Pharmacol 2001, 363: 166-174.
The study compounds were administered in a dose of 3 mg/kg in slow 5-minute intravenous perfusions. The haemodynamic and electrocardiographic parameters and the right and left auricular refractory periods were determined before and after administering the study compound.
In a dose of 3 mg/kg, the compounds of the invention generally abolished 100% of non-sustained fibrillation or auricular flutter episodes induced by early extra stimuli. In this dose, significant increases in the effective auricular refractory periods were observed for different basal values of the cardiac period.
IV. Effects of Cardiac Ion Channels
This test aims to determine the effects of the compounds of the invention on cardiac ion channels.
The compounds of the invention (1 to 5 μM) inhibited the permeability of human hERG (IKr) and hKv1.5 (IKur) gene channels expressed in the CHO (Chinese hamster ovary) cell line. They also inhibited native sodium (Ina), calcium (ICaL) and potassium channel currents, acetylcholine (IK(Ach))-activated and ATP-dependent (IKATP), in guinea pig cardiomyocytes, and potassium channels (Ito and Isus) in rat cardiomyocytes.
Thus, the compounds of the invention are inhibitors of multiple cardiac ion channels.
V. Toxicity
The toxicity of the compounds of the invention proved to be compatible with their therapeutic use.
VI. Solubility
The solubility tests for the compounds of the invention were carried out at pH=4 (starting from a phosphate buffer, pH=6, 0.1M) by HPLC (high performance liquid chromatography) using an H2O/CH3CN/CH3SO3H gradient and compared with a reference sample (a dilute solution of test product which acts as an internal reference).
The results for solubility, S, and pH are shown in the table below and are expressed in mg/ml.
In general, compounds with formula (I) of the present invention have a solubility of 1 mg/ml or more at pH=4; some of them had a solubility of more than 8 mg/ml or even more than 10 mg/ml.
TABLE OF EXAMPLEScompoundnosaltnR1R2AmS/pH 1  2  3  4  5  6hydrochloride oxalate hydrochloride oxalate oxalate hydrochloride3 3 3 4 4 4C4H9 C2H5 nC3H7 C4H9 C2H5 nC3H7H H H H H H8.81/5.4 7.47/4.07 >10/5.82 >10/4.10 >10/3.96 >10/5.79  7  8  9 10 11 12 13 14 15 16hydrochloride hydrochloride hydrochloride hydrochloride hydrochloride hydrochloride hydrochloride oxalate hydrochloride hydrochloride3 3 3 4 4 3 3 4 4 4C4H9 C2H5 C3H7 C4H9 C2H5 ipr CH3 ipr CH3 C3H7H H H H H H H H H H8.57/5.65 8.6/5.82 5.29/5.82 >10/5.81 >10/5.82 1.2/4.3 1.61/7.2 2.33/4.10 1.56/6.33 >10/5.81 17 18 19 20 21 22hydrochloride hydrochloride hydrochloride oxalate oxalate oxalate3 3 3 4 4 4C4H9 C2H5 C3H7 C4H9 C2H5 C3H7H H H H H H>10/4.88 6.51/5.42 4.07/5.27 2.95/4.02 6.9/4.08 4.08/4.58 23 24 25 26hydrochloride oxalate hydrochloride hydrochloride3 3 3 3C4H9 C2H5 ipr CH3H H H H>10/6.06 5.92/4.51 1.71/6.4 1.49/7.14 27 28 29 30 31 32oxalate hydrochloride hydrochloride hydrochloride oxalate hydrochloride4 4 3 4 4 4ipr CH3 C3H7 C4H9 C2H5 C3H7H H H H H H2.17/6.5 1.54/7.01 >10/5.94 >10/5.85 >10/4.05 5.64/5.60 33oxalate3C4H9H3.88/5.36 34oxalate3C4H9H5.02/4.14 35oxalate3C4H9H4.4/4.75 36 37hydrochloride hydrochloride4 3C3H7 C4H9H H2.24/6.3 1.78/7.14 38hydrochloride3C4H9H1.42/6.7compoundnosaltnR1R2AmS/pH39hydrochloride3C4H9H>10/4.22 40hydrochloride3C4H9H9.93/4.3 41oxalate3C4H9H7.19/3.95 42oxalate3C4H9H1.66/5.18compoundR2 innosaltnR1position 6AmS/pH43hydrochloride3C4H9CH34.46/5.65 44hydrochloride3C4H9C2H5>10/6.0545hydrochloride3C4H9CH35.8/5.95 46hydrochloride3C4H9C2H58.92/5.92
The following non-limiting examples illustrate the preparation of the compounds and compositions of the invention:
The proton magnetic resonance spectra (1H NMR) described below were recorded at 200 MHz in DMSO-d6 using the DMSO-d6 peak as the reference.
The chemical displacements δ are expressed in parts per million (ppm). The signals observed are expressed as follows: s: singlet; bs: broad singlet; d: doublet; dd: double doublet; t: triplet; dt: double triplet; q: quadruplet; qui: quintuplet; m: mass; mt: multiplet; sxt: sextuplet.